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Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques


Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody–envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires.

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Data availability

The atomic models and cryo-EM density maps generated during the current study have been deposited in the Protein Data Bank and Electron Microscopy Data Bank with accession numbers 6ORN and EMD-20175 (RC1–10-1074), 6ORQ and EMD-20178 (RC1–Ab275MUR), 6ORO and EMD-20176 (RC1–Ab874NHP), and 6ORP and EMD-20177 (RC1–Ab897NHP). Sequence datasets generated and analysed during the current study are available from the corresponding authors upon reasonable request.

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We thank members of the Bjorkman, Martin and Nussenzweig laboratories for discussions, T. Eisenreich and S. Tittley for animal husbandry, K. Gordon for flow cytometry, S. Zolla-Pazner for providing the V3-consensus C peptide and anti-V3 monoclonal antibodies, M. Howarth for providing plasmids and advice for VLP expression and purification and A. Malyutin for help with cryo-EM data collection. Cryo-EM was done in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) Grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), NIH Grant P50 GM082545-06 (to P.J.B.), NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (to M.C.N.), the Intramural Research Program of the NIAID (to M.A.M.), the National Center for Biomedical Glycomics P41GM103490 and NIGMS R01GM130915 (to L.W.), Gates CAVD grant OPP1146996 (to M.S.S. and D.C.M.), NIH/NIAID P01 AI138212 (to L.S., A.T.M. and M.C.N.) and the Robertson Fund of the Rockefeller University (M.C.N.). Additional support included an NSF GRFP (to M.E.A.), an EMBO fellowship (to J.M.), the HHMI Hanna Gray Fellowship and the Postdoctoral Enrichment Program from the Burroughs Welcome Fund (to C.O.B.). M.C.N. and D.J.I. are HHMI investigators.

Author information

A.E., H.B.G., P.J.B. and M.C.N. designed the research. A.E., H.B.G., M.E.A., J.M., R.G., C.O.B., A.A.C., H.W., J.G., D.Y., J.R.K., Z.W., P.Z., L.N., K.-H.Y., J.B., H.G., A.V.V. and M.S. performed the research. A.E., H.B.G., M.E.A., J.M., R.G., T.Y.O., J.P., A.P.W., P.J.B. and M.C.N. analysed the data. D.C.M. and M.S.S. supervised in vitro neutralization assays. A.G. supervised antibody production. M.A.M. planned and supervised the immunization experiments in macaques. D.J.I. planned and supervised adjuvant production. A.T.M. and L.S. produced anti-idiotypic antibodies. L.W. planned and supervised mass spectrometry experiments. A.E., H.B.G., M.E.A., P.J.B. and M.C.N. wrote the manuscript.

Competing interests

There are patents on 3BNC117 and 10-1074 on which M.C.N. and P.J.B. are inventors. M.C.N. is a member of the Scientific Advisory Boards of Celldex and Frontier Biosciences.

Correspondence to Pamela J. Bjorkman or Michel C. Nussenzweig.

Extended data figures and tables

Extended Data Fig. 1 RC1 characterization.

a, Comparison of geometric mean half-maximum inhibitory concentrations (IC50) for V3-glycan patch bNAbs (10-1074 and PGT121) and an N156 glycan-dependent V1V2 bNAb (BG1) evaluated against HIV-1 strains that either contained or did not contain a PNGS at the indicated positions (the number of HIV-1 strains is indicated in the parentheses). Values of IC50 greater than 50 μg ml−1 were set to 50 μg ml−1 for geometric mean calculations. Whereas V3-glycan patch bNAbs showed enhanced neutralization upon removal of the N156 glycan, removal of nearby glycans (N137 or N301) diminished or had little effect on neutralization. b, ELISA data showing the binding of different classes of bNAbs to RC1, RC1-4fill and BG505. bNAbs were evaluated at 5 μg ml−1 and seven additional threefold dilutions. n = 2. RC1 and RC1-4fill show similar binding patterns for V3-glycan patch bNAbs, CD4-binding site bNAbs (CD4bs) and gp120–gp41 interface bNAbs, but reduced binding to BG1, a V1V2 bNAb that interacts with the N156 glycan (see a).

Extended Data Fig. 2 Cryo-EM data collection and processing for RC1 complexes.

ad, A representative micrograph, selected two-dimensional class averages, orientation distribution summary, GSFSC resolution plot, local resolution (calculated using ResMap) and representative density maps contoured at 7σ for a gp41 helix and antibody CDRH3 are shown. a, The 10-1074–RC1 complex. b, The Ab275MUR–RC1 complex. c, The Ab874NHP–RC1 complex. d, The Ab897NHP–RC1 complex.

Extended Data Fig. 3 Antibody responses in wild-type mice.

a, ELISA cross-reactivity of serum from RC1-immunized wild-type mice to 11MUTB. Binding of the serum from wild-type mice primed with RC1 to RC1, 11MUTB, 10MUT and BG505 is shown in blue. Binding of the human bNAbs 10-1074 (green) and 3BNC117 (red) was evaluated at 5 μg ml−1 as a control. n = 2. b, FACS plots showing the gating strategy to isolate single RC1+RC1-glycanKO germinal centre B cells (DUMP (CD4, CD8, F4/80, NK1.1, CD11b, CD11c and Gr-1) B220+CD95+GL7+RC1-glycanKORC1+) from the spleen and draining lymph nodes of wild-type mice primed with RC1 or RC1-4fill. c, Binding of the mouse antibodies Ab275MUR and Ab276MUR to a V3 loop-consensus C peptide (see Methods). Human antibodies 3869 and 3074 were used as positive controls. Antibodies were evaluated at 30 μg ml−1. n = 2. d, Representative sensograms from two independent SPR-binding experiments of Ab275MUR Fab injected over immobilized RC1 (left) or 11MUTB (right). Experimental binding curves (red) are overlaid with predicted curves (black) derived from a 1:1 binding model. Representative of 3 independent experiments. e, Binding of Ab276MUR and its inferred germline version (Ab276MURGL) to RC1 (left) and RC1-glycanKO (right) at 30 μg ml−1. The human monoclonal antibodies PGT121 (green) and 3BNC60 (red) were used as controls at 5 μg ml−1.

Extended Data Fig. 4 Characterization of RC1, RC1-4fill and VLPs.

a, SEC profiles of RC1 and RC1-4fill showing a larger apparent hydrodynamic radius for RC1-4fill compared with RC1, consistent with addition of extra glycans at the introduced PNGSs. b, ELISAs showing comparable binding of PGT122 Fab to RC1 and RC1-4fill. RLU, relative luminescence unit. c, Glycan site occupancy for each PNGS in RC1 and RC1-4fill determined by mass spectrometry. d, SDS–PAGE analysis for RC1 and RC1-4fill under non-reducing (NR), reducing (R) and PNGaseF-treated (PNG) conditions. e, SDS–PAGE analysis for VLP, SpyTagged RC1-4fill and VLP-RC1-4fill under non-reducing and reducing conditions.

Extended Data Fig. 5 Characterization of antibody responses in macaques.

a, Binding of serum from macaques primed with RC1-4fill VLPs. ELISAs of the serum from eight macaques primed with RC1-4fill VLPs and PGT121 to RC1 (black) and RC1-glycanKO (grey) are shown. b, Binding of serum from macaques primed with RC1-4fill VLPs. ELISA of the serum from eight macaques primed with RC1-4fill VLP and one naive macaque to RC1 (black) and the sequentially less modified Env proteins 11MUTB (grey) and 10MUT (white). The human bNAbs PGT121 and 3BNC60 were used as controls at 5 μg ml−1, and the serum was evaluated at a 1:100 dilution and seven additional threefold serial dilutions. c, The affinities (KD) for RC1 of different macaque antibodies isolated after a prime with VLP-RC1-4fill and the corresponding inferred germline-reverted antibodies as determined by bio-layer interferometry (OCTET). d, Binding of an anti-idiotypic antibody that recognizes the inferred germline of PGT121/10-1074 to monoclonal antibodies isolated from macaques primed with VLP-RC1-4fill. The inferred germline (iGL) of PGT121/10-1074, two chimeric antibodies comprising the mutated (MT) heavy chain (HC) and inferred germline light chain (LC) of PGT121 (PGT121 HCMT-LC iGL) or the inferred germline HC and the mutated LC of PGT121 (PGT121HC iGL-LCMT) and different inferred germline bNAbs were used as controls. a, b, d, Results are shown as the area under the ELISA curve (AUC). e, Comparison of binding mode between the vaccine-elicited antibodies (Ab275MUR, Ab874NHP and Ab897NHP) and the V3-glycan patch bNAbs 10-1074, PGT128 and PGT135. RC1 trimer is shown in grey from above and all Fabs are modelled onto the same trimer. For clarity, only one Fab per trimer is shown. f, Interactions between Ab897NHP conserved light chain motifs and RC1 gp120. Lime, DNS motif in CDRL3; red, gp120 GDIR; pink, NIG motif in CDRL1; teal, gp120 V1 loop. Each AUC value corresponds to one ELISA curve.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Extended Data Table 2 HIV-1 Env-based proteins
Extended Data Table 3 Results of neutralization assays in TZM-bl cells
Extended Data Table 4 Mouse monoclonal antibodies
Extended Data Table 5 Immunoglobulin genes and CDRL3 amino acid sequences of V3-glycan patch bNAbs

Supplementary information

Reporting Summary

Supplementary Table 1

IgH gene sequences from single B-cells isolated from wild-type mice immunized with RC1 or RC1-4fill. Tables show the VH, DH and JH genes, CDRH3 amino acid (AA) sequence and length and the number of nucleotide (nt) mutations in the VH gene. Colors correspond to the expanded clones in Fig. 2i.

Supplementary Table 2

IgK gene sequences from single B-cells from wild-type mice immunized with RC1 or RC1-4fill. Table shows VH and JH genes, CDRL3 amino acid (AA) sequence and length, and the number of nucleotide (nt) mutations in the VK gene. Colors correspond to clusters of light chains.

Supplementary Table 3

IgH gene sequences from single B cells isolated from 4 macaques immunized with RC1-4fill VLPs. Tables show the VH, DH and JH genes, CDRH3 amino acid (AA) sequence and length, and the number of nucleotide (nt) mutations in the VH gene. Colors correspond to the expanded clones in Fig. 3i.

Supplementary Table 4

IgL gene sequences from single B cells isolated from 4 macaques immunized with RC1-4fill VLPs. Tables show the VH and JH genes, CDRL3 amino acid (AA) sequence and length, and the number of nucleotide (nt) mutations in the VL gene. Colors correspond to clusters of light chains.

Supplementary Table 5

Monoclonal antibodies isolated from macaques immunized with RC1-4fill VLPs. The antibodies that targeted the V3-glycan patch epitope of RC1 are indicated in the V3-glycan specificity column (V3-GL SPEC) with a YES. ND=no detectable binding to RC1. AA=Amino acid.

Supplementary Table 6

Primers used for IgH and IgL macaque gene amplification.

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Fig. 1: Characterization of the RC1 immunogen.
Fig. 2: Wild-type mouse immunization with RC1 elicits V3-glycan patch antibodies.
Fig. 3: Macaque immunization with RC1-4fill VLPs elicits anti-V3-glycan patch antibodies that resemble inferred germlines of bNAbs.
Fig. 4: Monoclonal antibodies from macaques bind to the V3-glycan patch.
Fig. 5: Structures of 10-1074 and elicited antibodies bound to RC1.
Extended Data Fig. 1: RC1 characterization.
Extended Data Fig. 2: Cryo-EM data collection and processing for RC1 complexes.
Extended Data Fig. 3: Antibody responses in wild-type mice.
Extended Data Fig. 4: Characterization of RC1, RC1-4fill and VLPs.
Extended Data Fig. 5: Characterization of antibody responses in macaques.


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